The major objective of the experiments outlined in this application is to elucidate the pathogenesis of glucose/diabetes-induced vascular dysfunction linked to increased metabolism of glucose via the sorbitol pathway. The general hypothesis to be tested is that diabetes-induced vascular dysfunction is mediated by metabolic imbalances resulting from increased flux of glucose via the sorbitol pathway. The specific aims of the proposed experiments are to: 1) assess the role of accumulation of long-chain fatty acyl esters (i.e., palmitoylcarnitine and palmitoyl CoA) in mediating sorbitol pathway-linked vascular dysfunction, 2) elucidate the nature of sex steroid-modulation of sorbitol pathway metabolism and vascular dysfunction, 3) test the hypothesis that vascular dysfunction caused by increased sorbitol pathway metabolism increases the susceptibility of the vasculature to injury by risk factors independent of diabetes (i.e., hypertension), and 4) test the hypothesis that a combination of pharmacologic agents which correct different metabolic imbalances resulting from increased sorbitol pathway metabolism should be more efficacious than any one of these pharmacologica agents alone in preventing vascular dysfunction caused by chronic diabetes. These questions and hypotheses will be investigated in animals with streptozotocin-induced diabetes as well as in in vitro studies of tissues removed from diabetic and nondiabetic animals. The impact of selected pharmacologic agents on diabetes-induced vascular dysfunction, i.e., increased blood flow (assessed by use of radiolabeled microspheres) and vascular permeation by radiolabeled albumin will be assessed in the eyes, peripheral nerve, and aorta prior to removal of tissues from these animals for assessment of the effects of pharmacologic agents on diabetes-induced changes in tissue levels of metabolites of interest.